Inhibitors selective for mycobacterial versus human proteasomes

Many anti-infectives inhibit the synthesis of bacterial proteins, but none selectively inhibits their degradation. Most anti-infectives kill replicating pathogens, but few preferentially kill pathogens that have been forced into a non-replicating state by conditions in the host. To explore these alt...

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Published in:	Nature (London) Vol. 461; no. 7264; pp. 621 - 626
Main Authors:	Lin, Gang, Li, Dongyang, de Carvalho, Luiz Pedro Sorio, Deng, Haiteng, Tao, Hui, Vogt, Guillaume, Wu, Kangyun, Schneider, Jean, Chidawanyika, Tamutenda, Warren, J. David, Li, Huilin, Nathan, Carl
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 01-10-2009 Nature Publishing Group
Subjects:	59 Antibacterial agents Antibiotics. Antiinfectious agents. Antiparasitic agents Bacteria Bacteriology Biological and medical sciences Catalytic Domain - drug effects Clinical medicine Degradation Fundamental and applied biological sciences. Psychology Human Humanities and Social Sciences Humans Hydrogen Bonding Inhibitor drugs Inhibitors Kinetics Medical sciences Metabolism. Enzymes Microbiology Models, Molecular multidisciplinary Mycobacteria Mycobacterium Mycobacterium tuberculosis Mycobacterium tuberculosis - drug effects Mycobacterium tuberculosis - enzymology Mycobacterium tuberculosis - growth & development Nitric oxide Oxazolidinones - metabolism Oxazolidinones - pharmacology Pathogens Pharmacology. Drug treatments Physiological aspects Protease Inhibitors - chemistry Protease Inhibitors - pharmacology Proteasome Endopeptidase Complex - chemistry Proteasome Endopeptidase Complex - metabolism Proteasome Inhibitors Protein Carbonylation - drug effects Protein Conformation - drug effects Protein Subunits Protein synthesis Replicating Science Science (multidisciplinary) Staphylococcus infections Substrate Specificity Suicide Thiazoles - pharmacology Threonine - metabolism Tuberculosis Ubiquitin-proteasome system United States Human Peptidases Multicatalytic endopeptidase complex Specificity Mycobacterium tuberculosis Enzyme Mycobacteriales Proteasome inhibitor Mycobacteriaceae Bacteria Hydrolases Actinomycetes
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Summary:	Many anti-infectives inhibit the synthesis of bacterial proteins, but none selectively inhibits their degradation. Most anti-infectives kill replicating pathogens, but few preferentially kill pathogens that have been forced into a non-replicating state by conditions in the host. To explore these alternative approaches we sought selective inhibitors of the proteasome of Mycobacterium tuberculosis . Given that the proteasome structure is extensively conserved, it is not surprising that inhibitors of all chemical classes tested have blocked both eukaryotic and prokaryotic proteasomes, and no inhibitor has proved substantially more potent on proteasomes of pathogens than of their hosts. Here we show that certain oxathiazol-2-one compounds kill non-replicating M. tuberculosis and act as selective suicide-substrate inhibitors of the M. tuberculosis proteasome by cyclocarbonylating its active site threonine. Major conformational changes protect the inhibitor-enzyme intermediate from hydrolysis, allowing formation of an oxazolidin-2-one and preventing regeneration of active protease. Residues outside the active site whose hydrogen bonds stabilize the critical loop before and after it moves are extensively non-conserved. This may account for the ability of oxathiazol-2-one compounds to inhibit the mycobacterial proteasome potently and irreversibly while largely sparing the human homologue. New anti-TB approach Proteasomes, protein complexes that break up superfluous or damaged proteins, are structurally conserved from archaea to eukaryotes. Proteasome inhibitors have been used in cancer therapy and suggested for the treatment of infections by eukaryotic pathogens, such as plasmodia and trypanosomes, but the inherent toxicity of proteasome inhibitors is a drawback in the treatment of curable infections. The mycobacteria are the only known bacterial pathogens with proteasomes and the discovery of a new class of small molecules that selectively inhibit Mycobacterium tuberculosis proteasomes raises the prospect that anti-proteasome agents might prove to be highly selective drugs for the treatment of tuberculosis. The new agents are oxathiazol-2-one compounds that bind irreversibly to the M. tuberculosis proteasome, while largely sparing the human homologue. Proteasome structure is extensively conserved across a broad range of organisms, so it is not surprising that inhibitors of all chemical classes tested have blocked both eukaryotic and prokaryotic proteasomes. However, certain oxathiazol-2-one compounds are now shown to kill non-replicating Mycobacterium tuberculosis and act as selective inhibitors of the M. tuberculosis proteasome while largely sparing the human homologue.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 NATIONAL INSTITUTE OF HEALTH BNL-90610-2009-JA DE-AC02-98CH10886 These authors contributed equally.
ISSN:	0028-0836 1476-4687
DOI:	10.1038/nature08357